Gilteritinib combined with venetoclax and azacitidine for relapsed acute myeloid leukemia cocurrent with pure red cell aplasia after allogeneic hematopoietic stem cell transplantation: a case report.

Pure red cell aplasia (PRCA) is a rare bone marrow (BM) disorder characterized by ineffective erythropoiesis, reduced reticulocyte count, normocytic anemia, and the absence of erythroid precursors. Here, we present a rare instance of PRCA occurring after ABO-matched allo-HSCT in a refractory/relapsed acute myeloid leukemia (R/R AML) patient. In this case, the patient received a combination treatment of Gilteritinib, Venetoclax, and Azacitidine. Remarkably, this treatment not only reduced myeloblasts but also facilitated the restoration of erythroid hematopoiesis.

En mann i 40-årene med transfusjonskrevende anemi.

BACKGROUND: While standard blood tests are often sufficient for an anaemia workup, sometimes more invasive diagnostic testing is required to exclude rare conditions. CASE PRESENTATION: A man in his forties contacted his general practitioner because of increasing functional dyspnoea. He had completed a course of dicloxacillin a few months previously for a skin abscess on his abdomen. Bloodwork revealed severe anaemia (haemoglobin 5.4 g/dL), which required transfusion. Subsequent testing excluded iron and vitamin deficiency anaemia, haemolysis and malignancy. Initial bone marrow biopsy was of suboptimal quality. However, repeat tissue sample supported a diagnosis of pure red cell aplasia. The patient improved with ciclosporin treatment, which was gradually tapered. INTERPRETATION: Pure red cell aplasia should be considered in patients with new onset isolated anaemia with severe reticulocytopenia. Diagnosis depends on obtaining representative tissue from bone marrow biopsy. It is difficult to conclude for this patient whether the aetiology of his pure red cell aplasia was idiopathic or secondary to recent dicloxacillin use.

Treatment strategy for acquired pure red cell aplasia: a systematic review and meta-analysis.

The treatment of autoimmune acquired pure red cell aplasia (aPRCA) is challenging. Guidelines are based on expert recommendations in the absence of controlled trials. We assessed the efficacy of the main treatment strategy through a systematic review and meta-analysis using MEDLINE, EMBASE, and the Cochrane Library up to September 2022. The overall response rate (ORR) was pooled using random-effects models. In total, 24 observational studies (19 retrospective, median follow-up of 48 months) encompassing 753 patients (49% male) were included. Primary aPRCA represented 57% of the cases. The risk of bias was moderate to high using the ROBINS-I tool. Substantial heterogeneity (I2 > 50%) was retrieved. Corticosteroids as monotherapy as first-line treatment (186 patients, 13 studies) provided an ORR of 47% (95% confidence interval [CI], 34-60). Cyclosporine A was the most frequently used immunosuppressant agent (384 patients, 18 studies), providing an ORR of 74% (95% CI, 66-82) with a similar ORR in first- (73%) and second-line (76%) treatment and when cyclosporin was used as monotherapy (83%) or with corticosteroids (77%). A total of 112 patients (10 studies) received cyclophosphamide, with an ORR of 49% (95% CI, 35-64), which was higher when cyclophosphamide was combined with corticosteroids (48%) and used in second-line treatment (58%) than in monotherapy (31%), and in first-line treatment (44%). Sirolimus use was reported only after cyclosporine A failure and provided an ORR of 87% (95% CI, 68-100; 64 patients, 3 studies). Substantial uncertainty remains regarding the best treatment strategy in the absence of high-quality evidence. This study was registered on the PROPERO database as #CRD42022360452.

Case report: Successful treatment with daratumumab for pure red cell aplasia in a patient with mixed lymphoid chimerism after ABO-mismatched stem cell transplant for sickle cell disease.

Pure red cell aplasia (PRCA) is a serious complication after ABO-mismatched allogeneic hematopoietic stem cell transplantation (HSCT). Following HSCT, persistent anti-donor isohemagglutinins against donor ABO antigens are considered the immunological cause of PRCA. Patients with post-transplant PRCA are at risk for graft rejection and prolonged red blood cell transfusion dependency. No standard treatment exists. Recently however, the anti-CD38 monoclonal antibody daratumumab has been reported to be an effective treatment for post-transplant PRCA in patients with complete donor chimerism. Here, we describe the first case of PRCA in a patient with mixed lymphoid patient/donor chimerism that was successfully treated with daratumumab. This is also the first report of a transplant recipient with sickle cell disease who was treated with this relatively new approach. Fourteen months post-transplantation and twelve months after treatment with daratumumab, our patient has a normal complete blood count and the anti-donor isohemagglutinins remain undetectable despite mixed lymphoid chimerism. Mixed chimerism is a common manifestation in adult patients with sickle cell disease transplanted with non-myeloablative conditioning and a matched sibling donor. The application of non-myeloablative HSCT for patients with sickle cell disease is steadily increasing. Therefore, the incidence of PRCA in this setting might also increase. As the risk of graft rejection due to PRCA can be especially high in patients with mixed chimerism, clinicians should be aware that daratumumab can be an effective treatment in the setting of mixed chimerism.

Donor-type red blood cell transfusion to deplete isoagglutinins prior to allogeneic stem cell transplantation from ABO major incompatible bone marrow donors.

ABO incompatibility affects approximately 40% of allogeneic stem cell transplants in Caucasian patient populations. Because bone marrow (BM), the preferred graft from paediatric sibling donors and for non-malignant diseases, has a red blood cell (RBC) content similar to blood, anti-donor isoagglutinins must either be depleted from the recipient or RBCs removed from the graft. To achieve tolerability of unmanipulated BM grafts, we used controlled infusions of donor ABO-type RBC units to deplete isoagglutinins before the transplant. This retrospective study evaluates the outcomes of 52 ABO major incompatible BM transplants performed at our centre between 2007 and 2019. The use of donor-type RBC transfusions was well tolerated. They effectively reduced isoagglutinins levels, typically achieving target titres after one (60%) or two (29%) transfusions. The approach allowed for successful and uneventful infusions of unmanipulated BM which provided timely engraftment. The transplant outcomes were not inferior to those of a matched-pair control group of patients with ABO-identical donors.

[Pure red cell aplasia: Diagnosis, classification and treatment]. / L'érythroblastopénie : diagnostic, classification, traitement.

Pure red cell aplasia (PRCA) is a rare anemia characterised by profound reticulocytopenia caused by a marked reduction in bone marrow erythroblasts, without abnormalities in other blood lineages. Blackfan-Diamond anemia is an inherited ribosomopathy responsible for a hereditary form of PRCA. Acquired PRCA are separated in primary and secondary forms, including Parvovirus B19 infection, thymoma, lymphoproliferative disorders, autoimmune diseases (lupus) and drug-induced PRCA. The pathophysiology of PRCA is not fully understood and involves both humoral and T lymphocyte autoreactive cells. In Parvovirus B19-related PRCA, treatment is based on polyvalent immunoglobulins. Thymectomy for thymoma is mandatory but results in prolonged remission in a limited number of cases. The therapeutic strategy is based on expert opinion: corticosteroids in monotherapy provide few sustained responses. The choice of an additional immunosuppressant drug is guided by the presence of an underlying disease. In most cases, cyclosporine A is the first choice providing the best response rate but requires a concentration monitoring (150 to 250 ng/mL). The second choice is cyclophosphamide in large granular lymphocyte leukaemia. Sirolimus (mTOR inhibitor) seems to be a promising option especially in refractory cases. Transfusion independence is the main objective. If the patient receives numerous red blood cell transfusions (> 20 packs), iron overload assessment is crucial to initiate an iron chelation. A retrospective and prospective national cohort (EPIC-F) has been set up and is now available to include each case of PRCA to improve the knowledge of this disease and to optimize the therapeutic strategy.

[ABO incompatibility and complications in hematopoietic stem cell transplantation]. / Incompatibilidad ABO en el trasplante de células progenitoras hematopoyéticas y sus complicaciones.

Background: Hematopoietic stem cell transplants (HSCT) can be performed regardless of the ABO group compatibility between donor and recipient. ABO incompatibility in HSCT is related to pure red cell aplasia (PRCA), or passenger lymphocyte syndrome. The impact of ABO incompatibility on graft-versus-host disease and transplant-related mortality is controversial due to the heterogeneity of procedures carried out in different transplant centers. Objective: To determine the prevalence of ABO incompatibility and its complications in a hematopoietic stem transplant unit. Material and methods: An observational, retrospective study was carried out in patients undergoing HSCT from January 2014 to January 2020. All trasplant patients were included. Qualitative variables were analyzed using chi-squared test, and Wilcoxon and Student's t tests were used for quantitative variables. A p < 0.05 was considered significant. Results: 124 patients undergoing HSCT were analyzed, out of which 31 had ABO incompatibility, with a punctual prevalence of 24.4%; among them, 54% presented with major incompatibility, 32% minor incompatibility and 13% bidirectional incompatibility. Three cases of PRCA were reported. There were no differences in survival at one year in both groups. Conclusions: The ABO incompatibility ant its complications were not related to the increase in mortality. Randomized prospective studies are required to define the role of ABO incompatibility in HSCT prognosis.

Introducción: los trasplantes de células progenitoras hematopoyéticas (TCPH) se pueden hacer independientemente de la compatibilidad de grupo sanguíneo ABO entre donador y receptor. La incompatibilidad ABO (IABO) en los TCPH puede presentar complicaciones, como aplasia pura de serie roja (APSR), o síndrome de linfocito pasajero. El impacto de la IABO en la enfermedad del injerto en contra del huésped y la mortalidad relacionada al trasplante es controversial por la heterogeneidad de procedimientos que se hacen en los distintos centros de trasplante. Objetivo: determinar la prevalencia de la IABO y sus complicaciones en los pacientes trasplantados en una unidad de trasplante de progenitores hematopoyéticos. Material y métodos: se hizo un estudio tipo observacional, descriptivo, en pacientes sometidos a TCPH de enero de 2014 a enero de 2020. Se incluyeron todos los pacientes trasplantados. Las variables cualitativas se analizaron con chi cuadrada y para las variables cuantitativas se usó la prueba de Wilcoxon y t de Student. Una p < 0.05 fue significativa. Resultados: se analizaron 124 pacientes sometidos a TCPH y 31 de ellos presentaron IABO, con una prevalencia puntual de 24.4%; entre ellos, 54% presentaron incompatibilidad mayor, 32% incompatibilidad menor y 13% incompatibilidad bidireccional. Se reportaron tres casos de APSR. No hubo diferencias en la supervivencia global a un año en ambos grupos. Conclusiones: la IABO y sus complicaciones no se relacionaron con aumento en la mortalidad. Se requieren estudios prospectivos aleatorizados para definir el papel de la IABO con el pronóstico del trasplante.

Case report: Dynamic antibody monitoring in a case of anti-recombinant human erythropoietin-mediated pure red cell aplasia with prolonged course after kidney transplantation.

Anti-erythropoietin (anti-EPO) antibody-mediated pure red cell aplasia (PRCA) is a rarely seen disease. Anti-EPO antibodies were mostly found in patients with chronic kidney disease who received recombinant human erythropoietin (rHuEPO) injections subcutaneously. The treatment against anti-EPO antibody-mediated PRCA included discontinuation of rHuEPO, immunosuppressive agents, intravenous immunoglobulin, plasmapheresis, or kidney transplantation. We reported a case of kidney transplant recipient with anti-EPO antibody-mediated PRCA, who had no trend of recovery after stopping rHuEPO, receiving regular induction and maintenance immunosuppressive regimens. He was further given 6 consecutive plasmapheresis sessions, cyclophosphamide, and adjusted maintenance immunosuppressive regimen into cyclosporine, sirolimus and prednisone. We monitored his anti-EPO antibody levels with a self-created simple mixing test. At 10 months post kidney transplant, his anti-EPO antibody finally turned negative, and his reticulocyte count dramatically increased. Cyclosporine, sirolimus and prednisone combined with roxadustat eventually alleviated the patient's anti-EPO antibody-mediated PRCA. Our self-created simple mixing test for anti-EPO antibody titer was very helpful in disease monitoring and therapeutic guidance.

Clinical Update.

Parvovirus B19 is notoriously a cause of normocytic anaemia in patients in an immunocompromised state, more so than in patients without prior disease. It is increasingly prevalent in children and adults in an HIV-induced immunocompromised state, and its presentation may be varied. Red-cell aplasia and normocytic anaemia are common presenting derangements found. Here, we note the typical presentation of red-cell aplasia re-entering healthcare, with a dire effect on the quality of life of this patient.

Isolated Anemia in a 69-Year-Old Man with HIV-1: Features of Pure Red Cell Aplasia Mediated by Chronic Parvovirus-B19 Infection.

BACKGROUND Pure red cell aplasia (PRCA) is an uncommon syndrome characterized by ineffective erythropoiesis and severe anemia. Among immunodeficient patients, including those with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), persistent parvovirus-B19 can cause PRCA. We report a rare case of an Australian man with parvovirus-B19 mediated PRCA secondary to a new diagnosis of HIV-1/AIDS. The case highlights the importance of early treatment initiation with anti-retroviral drugs and pooled immunoglobulins to enable marrow recovery and long-term disease remission. CASE REPORT A 64-year-old man residing in rural Indonesia presented with severe anemia. Apart from 8 kg of unintentional weight loss, he denied any occult bleeding, diatheses, or constitutional symptoms. His bloodwork revealed a normocytic, normochromic anemia (Hb 81 g/L) with profound reticulocytopenia (9.5×109/L). Parvovirus-B19 serology and polymerase chain reaction testing confirmed active viremia. Lymphopenia and an undetectable CD4 T-lymphocyte count (<1%) were also noted; HIV-1 was subsequently diagnosed. Bone marrow sampling later confirmed features consistent with parvovirus-B19-driven PRCA secondary to HIV-1/AIDS. The patient received 1 g/kg intravenous immunoglobulin for two days and initiated anti-retroviral HIV therapy. Rapid reticulocytosis with slow incrementation of his hemoglobin were observed over one month. At three years following his diagnosis, he remains in remission. CONCLUSIONS Severe, isolated anemia in immunodeficient patients, particularly those with HIV-1/AIDS, should prompt consideration of parvovirus-B19-mediated PRCA. Depletion of CD4-T-lymphocyte populations enables the establishment of parvovirus-B19 reservoirs within erythroid progenitors, thereby hampering physiological erythropoiesis. Long-term remission can be achieved with the rapid institution of intravenous immunoglobulin and anti-retroviral HIV therapies.

A 46-Year-Old Thai Woman with Secondary Acquired Pure Red Cell Aplasia Due to Treatment with Recombinant Erythropoietin While on Dialysis for End-Stage Renal Disease Who Recovered Following ABO-Incompatible Kidney Transplantation.

BACKGROUND Pure red cell aplasia (PRCA) is an uncommon cause of anemia in end-stage kidney disease (ESKD). It is attributed to recombinant human erythropoietin (rHuEPO) administration. Although immunosuppression is the mainstay therapy, its effectiveness varies from 30% to 70%. PRCA in ESKD has been reported to improve following kidney transplantation. CASE REPORT A 46-year-old woman with ESKD secondary to lupus nephritis was treated for uremia at our center. She developed severe anemia. Bone marrow aspiration and biopsy revealed a reduction of erythroid precursors, consistent with PRCA. Because she had no sibling's blood group matched with her, ABO-incompatible kidney transplantation was an option for treatment. She underwent a desensitization protocol consisting of rituximab 375 mg/m2, tacrolimus, mycophenolate mofetil, and prednisolone 4 weeks before surgery, in addition to 3 sessions of double-filtration plasmapheresis (DFPP) every other day followed by intravenous immunoglobulin (IVIG) and 1 session of specific immunoadsorption (Glycosorb® B column) at pre-transplant day -1. She also received low-dose rabbit anti-thymocyte globulin (rATG) (Thymoglobulin®) (total 2.0 mg/kg). Maintenance therapy included tacrolimus, mycophenolate mofetil, and prednisolone. Allograft function normalized a few days after transplantation and her Hb gradually increased. CONCLUSIONS We report a rare case of PRCA in a patient with ESKD undergoing ABO-incompatible kidney transplantation. The outcome was satisfactory, with complete correction of anemia and kidney function.

Incidence of acquired pure red cell aplasia: a nationwide epidemiologic analysis with 2 registry databases in Japan.

Acquired pure red cell aplasia (PRCA) is a rare syndrome characterized by anemia with reticulocytopenia and a marked reduction in erythroid precursors. Given its rarity, the true incidence is largely unknown, and epidemiological data representing the general population, with a description of the full spectrum of etiologies, are scarce. An epidemiological study on PRCA in Japan conducted 30 years ago estimated the annual incidence as 0.3 per million. To update the data and investigate the incidence and demographics of PRCA, we conducted a nationwide epidemiological study using the Japanese Society of Hematology (JSH) Hematologic Disease Registry, a hematologic disease registration database managed by the JSH and the Diagnosis Procedure Combination (DPC) study data available at a website of the Ministry of Health, Labor, and Welfare (MHLW) of Japan. A total of 1055 patients with newly diagnosed acquired PRCA were identified between 2012 and 2019, and the average annual incidence was calculated at 1.06 (95% confidence interval [CI], 0.83-1.28) per million. The median age was 73 (range, 18-99) years. The female-to-male ratio was 1.5:1, and the female predominance was most prominent in the child-bearing age group. Sixty-nine percent of acquired PRCA was idiopathic. The incidence of PRCA was approximately 20% of that of aplastic anemia (AA) during the same period. Approximately 0.98 patients per million per year (95% CI, 0.89-1.07) required hospitalization for the treatment of PRCA. These results are expected to contribute to the discussion of resource allocation for PRCA in the aging population in many countries, including Japan.

Pure Red Cell Aplasia in a Renal Transplant Recipient: Case Report and Review of the Literature.

Severe anemia requiring multiple blood transfusions in the posttransplant period can trigger rejection. The evaluation of anemia among transplant recipients is a challenging task. Awareness should be continued for tacrolimus to manage pure red cell aplasia, but further evidence is needed to prove whether tacrolimus is a real cause of posttransplant anemia. Our case patient, a 66-year-old male patient with end-stage renal disease due to diabetic nephropathy, underwent a preemptive living donor renal transplant in September 2018. He had received a coronary artery bypass graft with transcatheter aortic valve implantation 3 years before renal transplant. Initially, he was maintained on prednisolone, mycophenolate mofetil, and tacrolimus after basiliximab induction. One month later, he presented with low cardiac output symptoms. His complete blood count showed normocytic normochromic anemia with reticulocytopenia (his hemoglobin level dropped from 112 to 69 g/L), which necessitated regular blood transfusions. His iron profile, serum folate, and vitamin B12 were within normal limits, and he had negative hemolytic and autoimmune screening tests. A bone marrow biopsy revealed acquired pure red cell aplasia, which was most likely drug induced as viral profiles were negative for parvovirus B19, cytomegalovirus, and Epstein-Barr virus. The patient was managed by discontinuing mycophenolate mofetil, and the steroid dose was increased up to 20 mg/day but without improvement. With tacrolimus then considered, 3 weeks after presentation, we replaced tacrolimus with cyclosporine. Complete blood count follow-up showed improvement without any need for further blood transfusions. After 1 month of cyclosporine maintenance, mycophenolate mofetil was resumed with a steady increase of hemoglobin up to 150 g/L and serum creatinine of 122 µmol/L. Pure red cell aplasia is a rare disorder among renal transplant recipients, which could be induced by maintenance tacrolimus therapy.

Prevalence of Pure Red Cell Aplasia Following Major ABO-Incompatible Hematopoietic Stem Cell Transplantation.

Background: Pure red cell aplasia (PRCA) is one of the important complications in major ABO-incompatible allogeneic hematopoietic stem cell transplantation (HSCT). The established pathogenic factor of PRCA is the persistence of high anti-donor isohemagglutinins. As previously verified, the conditioning regimen and donor type were the factors associated with the development of PRCA in the small-sized studies. Currently, the prevalence, risk factors, and prognosis of PRCA are still worth studying to provide evidence. Methods: We conducted a prospective nested case-control study to determine the prevalence, donor-related factors, and the outcomes of PRCA following major ABO-incompatible transplantation. A total of 469 patients who underwent ABO-incompatible grafts were observed. Results: None of the patients were diagnosed with PRCA with minor or bidirectional ABO-incompatible HSCT. Thirteen of the187 patients (7%; 95% confidence interval [CI], 3.9%-11.9%) developed PRCA following major ABO-incompatible HSCT. Eleven of the 13 patients with PRCA recovered entirely. Donor type was an independent factor associated with post-HSCT PRCA (odds ratio [OR]=0.030; 95% CI, 0.003-0.321; P=0.004). The cumulative incidence rates of post-HSCT PRCA in the context of major ABO-incompatible HSCT were 0.8%, 13.1%, and 27.2% for the haploidentical donor (HID), unrelated donor, and matched related donor, respectively. No significant influence of PRCA on transplantation outcomes was observed.In conclusion, post-HSCT PRCA is a rare and less threatening complication in major ABO-incompatible HSCT. The majority of patients with PRCA could recover. Additionally, HIDs for recipients may have a low risk of post-HSCT PRCA. This trial was registered at www.chictr.org.cn (#ChiCTR2000041412).

Roxadustat Improves Erythropoietin Antibody-Mediated Pure Red Cell Aplasia in a Patient with Hemodialysis.

Anemia is a common complication of chronic kidney disease (CKD). Recombinant human erythropoietin (rHu-EPO) is used extensively in patients with CKD. However, anti-erythropoietin (anti-EPO) antibody has been reported during rHu-EPO treatment, which causes pure red cell aplasia (PRCA). We presented a case of 75-year-old man, who underwent hemodialysis for 2 years. He developed PRCA during rHu-EPO treatment. The rHu-EPO was immediately discontinued, and the patient was given roxadustat treatment. After 6 months of roxadustat treatment, the anti-EPO antibody was disappeared, and hemoglobin recovered normal range. The results suggest that roxadustat can be used to treat patients with anti-EPO antibody-mediated PRCA without immunosuppressive therapy.

True thymic hyperplasia causing pure red cell aplasia: a case report.

Pure red cell aplasia caused by true thymic hyperplasia is extremely rare. We report the case of a 25-year-old female diagnosed with pure red cell aplasia. Following a thymectomy confirming true thymic hyperplasia and corticosteroid therapy, complete response was achieved. Patients diagnosed with pure red cell aplasia should be investigated with a computerized tomographic scan to assess for thymic pathology and if present, this should be resected. Follow-up is essential to monitor for recurrence.